Field
The present invention relates to certain disubstituted 1,5-naphthyridine and quinoline compounds as inhibitors of monamine oxidase, and monoamine oxidase B in particular; derivatives of such compounds; compositions of such compounds; methods of making them; and their use in various methods, including detection and imaging techniques; enhancing neuronal plasticity; treating neurological disorders, including neurodegenerative and cognitive disorders; providing neuroprotection; enhancing the efficiency of cognitive and motor training; facilitating neurorecovery and neurorehabilitation; and treating peripheral disorders, including obesity, diabetes, cardiometabolic disorders, and their associated co-morbidities.
Description of the Related Technology
Monoamine oxidase (MAO, E.C. 1.4.3.4) is a mitochondrial-bound, flavin-containing, enzyme that catalyzes the oxidative deamination of biogenic (endogenous) and xenobiotic (exogenous) amines. Biogenic amines can be divided into three categories: monoamines, such as serotonin (5-hydroxytryptamine, 5-HT) and tryptamine; catecholamines, such as dopamine (DA), norepinephrine (NE), and epinephrine; and trace amines such as beta-phenylethylamine (PEA), tyramine, and octopamine.
Oxidative deamination by MAO requires the cofactor FAD and results in formation of the corresponding aldehyde, which then is usually rapidly oxidized into a carboxylic acid by aldehyde dehydrogenase (ALDH). The byproducts of these reactions include potentially neurotoxic species, such as hydrogen peroxide and ammonia. Hydrogen peroxide, for example, can trigger the production of reactive oxygen species (ROS) and induce mitochondrial damage and neuronal apoptosis. Proper regulation of MAOs therefore appears crucial in maintaining proper nervous system function.
There are two MAO isoforms (types A and B), corresponding to the mao-A and mao-B genes, and they show distinct expression patterns (e.g., Riederer et al., J. Neural Transm. 1978, 43, 217-226; Saura et al., J. Neural Transm. Suppl. 1990, 32, 49-53; and Saura et al., Neuroscience 1996, 70, 755-774). In peripheral tissues, MAO-A is primarily found in the liver and gastrointestinal tract, whereas MAO-B is primarily found in blood platelets. In the human brain, MAO-A is predominantly expressed in catecholaminergic neurons, whereas MAO-B is mostly concentrated in astrocytes and astroglia but also expressed in serotonergic neurons, histaminergic cells, and astrocytes. MAO-A and MAO-B also display overlapping but distinct substrate preferences: Both forms show a similar preference for dopamine (DA), tyramine, and tryptamine; however, MAO-A preferentially metabolizes serotonin (5-HT) and noradrenaline (NE), whereas MAO-B preferentially metabolizes histamine and phenethylamine.
The ability of MAO enzymes to rapidly degrade brain monoamines such as 5-HT, NE, and DA is essential for proper synaptic neurotransmission. Monoaminergic signaling is a key mechanism for modulating mood and emotion, as well as controlling motor, perceptual and cognitive functions. More generally, MAO-B levels in the brain naturally increase with age, with significant increases observed after 50 to 60 years of age. Increases in MAO-B contribute to cellular degeneration by producing hydrogen peroxides that are converted by iron to highly toxic oxygen free radicals and leads to cell death. Likewise, perturbations in MAO activity are associated with numerous pathological processes. For example, increased MAO-B activity in the brain has been observed in Alzheimer's and Parkinson's patients, implicating oxidative damage in neurodegenerative and cognitive dysfunction (e.g., Fowler et al., J. Neural. Transm, 1980, 49, 1-20; Dostert et al., Biochem. Pharmacol. 1989, 38, 555-561; and Emilsson et al., Neurosci. Lett. 2002, 326, 56-60).
These observations highlight the interest in MAO-inhibition as a therapeutic target for numerous disorders (e.g., Bentue-Ferrer et al., CNS Drugs, 1996, 217-236). By increasing the concentration of monoamines present within the brain synapses, MAO inhibitors can enhance monoamine-mediated neurotransmission, effectively treating neurological and psychiatric disorders such as Parkinson's disease and depression. In addition, because MAO inhibitors have demonstrated antioxidant and anti-apoptotic activity in experimental models, they may offer neuroprotective benefits by curbing the production of toxic oxidative species during MAO catalysis (e.g., Youdim et al., Nat. Rev. Neurosci. 2006, 7, 295-309; Al-Nuaimi et al., Am. J. Ther. 2012, 19, 436-448.
A wide variety of MAO inhibitors been reported, including phenylcoumarine derivatives (ES2343347, Jul. 28, 2010), substituted azole derivatives (International Publication No. WO 2010098600, Sep. 2, 2010), axabenzoxazole derivatives (WO 2010051196, May 6, 2010), pyrazole derivatives (US20070203154, Aug. 30, 2007), benzopyran derivatives (WO 2006102958, Oct. 5, 2006), pyrrolidinylphenyl benzyl ether derivatives (WO 2006097270, Sep. 21, 2006), benzyloxybenzazepine derivatives (WO 200503951, May 6, 2005), arylpyrrolidinone derivatives (WO 200402687, Apr. 1, 2004), and substituted oxadiazole derivatives (EP504574, Sep. 23, 1992).
However, MAO inhibitors have generally been associated with numerous side effects that have typically limited their usefulness and tolerability. The first generation of MAO inhibitors—initially introduced in the 1950s for treating depression—was irreversible and non-selective. Use of these inhibitors was gradually abandoned mainly due to their potential for drug-drug and drug-food interactions, the most widely known being with tyramine-containing food (the ‘cheese’ effect). Moreover, when MAO inhibitors are used in high dosage, cardiovascular effects seem to increase considerably, and because MAO selectivity is lost with such high doses, tyramine can induce potentially dangerous hypertensive reactions. More recent drugs, including selegiline and rasagiline, show greater selectivity for MAO-B and may have better side effect profiles, but they still suffer from limitations owing to irreversible binding (Chen and Swope, J. Clin. Pharmacol. 2005, 45, 878-894).
It is therefore desirable to develop improved MAO inhibitors such as those showing higher potency, greater specificity, and better side effect profiles. The present invention meets these and other needs in the art by disclosing substituted naphthyridine and quinoline compounds as inhibitors of MAO, and more particularly, MAO-B.